Chronic lymphocytic leukemia is incurable using currently available therapy. We have explored the use of high dose therapy and either autologous or allogeneic stem cell transplantation (SCT). However, since most patients are elderly age, these approaches are not suitable for the majority of patients with CLL. There is therefore a need for novel treatment strategies in this disease. The central goal of Project 4 is to study the mechanisms whereby there is no efficient T cell mediated immune response against the leukemic cells in this disease. Understanding of the mechanisms whereby this tumor evades immune recognition should allow us to optimize methodologies to generate and expand tumor specific T cells ex vivo for adoptive immunotherapy. We believe that several problems have to be overcome. In this disease there are defects in T cell function that have to be understood before they can be corrected effectively. There are defects in the tumor cells and in particular in their capacity to present antigens to T cells. We aim to develop methodologies to expand autologous and allogeneic tumor specific T cells and translate these findings into clinical trials examining the role of autologous and allogeneic T cell tumor specific immunotherapy to develop novel treatment strategies that if successful should have minimal toxicity. To achieve this goal, Five Aims are proposed. First, to study the mechanism of T cell immunosuppression or anergy in CLL. Second, to examine signaling events in the CLL cells involved in induction of efficient antigen presenting capacity . Third, to develop and optimize methods to generate and expand autologous and allogeneic tumor specific T cells for minimal disease state. Fifth, to translate these observations to clinical trials of tumor specific immunotherapy in potential tumor antigens, Projects 2, 5 and 6 to study the impact of therapy on CLL and T cell function. This project is highly interactive with Project 3, and is dependent upon the Clinical, Biostatistical and Tissue Specimen Cores.